Role of calcium-dependent K+ channels in the regulation of arterial and venous tone by nitric oxide in pigs

Effects of inhibition of calcium-dependent potassium channels (K⁺ _Ca channels) on the regulation of arterial and venous tone by nitric oxide (NO) were studied in anaesthetized pigs following vagotomy and blockade of autonomic ganglia. Selective inhibition of K⁺ _Ca channels by charybdotoxin (CTX, 2 μg/kg iv) or iberiotoxin (IbTX, 1 μg/kg) significantly augmented mean total peripheral resistance (TPR) to levels 30–60% above control. Venous and pulmonary vascular tone were assessed by changes in effective compliances of the venous (EVC) and pulmonary (EPC) vascular beds as calculated from changes in central venous and diastolic pulmonary arterial blood pressure during haemorrhagia (−5 ml/kg) and hypervolaemia (+5 ml/kg). Blockade of K⁺ _Ca channels significantly decreased both EVC (−20 to −30%) and EPC (−30 to −50%). Both CTX and IbTX significantly diminished the vasodilation caused by the NO-donor S-nitroso-N-acetylpenicillamine (SNAP) both during control conditions and following experimental vasoconstriction induced by systemic inhibition of NO-synthesis by NG-nitro-L-arginine methyl ester (L-NAME) or infusion of vasoconstrictor agonists. Dilator effects of the adenosine 3′,5′-cyclic monophosphate (cAMP)-dependent agonist adenosine were only slightly reduced. However, blockade of K⁺ _Ca channels did not increase vasoconstriction induced by L-NAME significantly. These results suggest that activation of vascular K⁺ _Ca channels is an important mechanism by which NO attenuates the constrictor tone of resistance and capacitance vessels in vivo. + _Ca channel blockade during vasoconstriction by agonists The effects of CTX on the haemodynamic responses to infusions of AII, AVP, NA and ET-1, at doses producing similar increases in MAP of about 50 mmHg, are listed in Table 1. The increase in TPR caused by NA and ET-1 was significantly smaller after CTX, whereas the responses to AII and AVP were similar both before and after CTX. To characterize this effect of K⁺ _Ca channel blockade further, we constructed dose-response curves for AII and NA with and without pretreatment with IbTX. The results for TPR are shown in Fig. 5. The constrictor responses to the two lower doses of NA were significantly reduced by IbTX. Received: 12 February 1996 / Accepted: 31 March 1996